Epilepsy affects about 2.5 million people in the USA and 40 million worldwide. Of this population 40% are patients with temporal lobe Epilepsy (TLE). In approximately 45% of those with TLE, seizures cannot be well controlled by available medications. Surgery helps a proportion of these patients, but remains a costly procedure with a risk of morbidity. The molecular mechanisms of TLE are not yet fully elucidated, but if better known could provide new avenues for the treatment and/or cure of this disease. Recent developments in methods for high throughput screening of gene (genomics) and protein (proteomics) expression hold promise of more rapid progress in unravelling these molecular mechanisms. We have begun to identify various genes and pathways associated with the pathophysiology of epileptic brain foci from TLE patients supported by a recently received R21. However, gene expression analyses do not by themselves provide reliable information on the actual proteins encoded by identified genes. A single gene can encode many different protein species due to differences in editing and splicing, and their products may show post- translational modification. In this proposal we propose to analyze the proteome in hippocampal seizure foci, to complement genomic studies in progress. In these studies we will use 2-DIGE analyses to identify the protein profile that characterizes mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE). In patients with paradoxical temporal lobe epilepsy (PTLE), where only one in two patients experience seizure free status after surgery, proteomic profiles will be compared with surgical outcome, to elucidate the proteome of the poor responders, as a means to developing a presurgical molecular diagnosis of this group. These studies are essential to identify molecules unique to TLE, which will be the candidates for study in future research that explores their role(s) in seizure mechanisms. [unreadable] [unreadable] [unreadable]